1-Phenyl-2-heteroaryl-substituted benzimdazole derivatives, their use for the production of pharmaceutical agents as well as pharmaceutical preparations that contain these derivatives

ABSTRACT

New benzimidazole derivatives are described, their production and their use for the production of pharmaceutical agents for treatment and prevention of diseases that are associated with a microglia activation and T-cell-mediated immunological diseases, as well as pharmaceutical preparations that contain the new benzimidazole derivatives.

[0001] This application claims the benefit of the filing date of U.S.Provisional Application Serial No. 60/357,834, filed Feb. 21, 2002.

[0002] The invention relates to new benzimidazole derivatives, theirproduction and their use for the production of pharmaceutical agents fortreating and preventing diseases that are associated with a microgliaactivation and of T-cell-mediated immunological diseases, as well aspharmaceutical preparations that contain the new benzimidazolederivatives.

[0003] The immune system comprises a considerable number of cells andtissue complexes that mainly communicate with one another via solublefactors. It is known that many immunological diseases are triggered byan imbalance of soluble immune factors, such as, e.g., the cytokines(Mosmann and Coffmann., Ann. Rev. Immunol. 7: 145-173 (1989 Street andMosmann, FASEB J. 5: 171-177 (1991); Lucey et al., Clin. Microbiol. Rev.4: 532-562 (1996); Powrie and Coffman, Trends Pharmacol. Sci 14: 164-168(1993); Singh et al., Immunolog. Res., 20: 164-168 (1999)). There are,for example, a considerable number of references to a role of interferongamma and interleukin 12 in the pathogenesis of autoimmune diseases.Especially to be cited are diseases that are characterized by aT-cell-mediated inflammatory reaction, such as multiple sclerosis,diabetes, chronic inflammatory intestinal diseases (inflammatory boweldiseases). The cytokine interleukin 12 (IL 12) is produced fromphagocytic cells, such as macrophages/monocytes, dendrites, B cells andother antigen-presenting cells (APC) and influences both the function ofnatural killer cells (NK cells) and those of T-lymphocytes. In both celltypes, TL 12 can stimulate the production of interferon gamma (IFNγ).T-Lymphocytes can be divided roughly into two categories that arecharacterized by the expression of certain surface antigens (CD4 andCD8): CD4-positive T cells (helper T cells) and CD8-positive T cells(cytotoxic T cells). The CD4 cells can in turn be divided into T-helpercells 1 (Th1) and T-helper cells 2 (Th2). Especially the Th1-mediatedimmunological responses are associated with the pathogenesis of numerousimmune diseases, especially the autoimmune diseases, such as, e.g.: typeI insulin-dependent diabetes mellitus (IDDM), multiple sclerosis,allergic contact dermatitis, psoriasis, rheumatoid arthritis, chronicinflammatory intestinal diseases (“inflammatory bowel diseases”—Crohn'sdisease, colitis ulcerosa), lupus diseases and other collagenoses aswell as acute rejection reactions in allografts(“host-versus-graft”—allograft rejection, “graft-versus-host disease”).

[0004] Of interleukin 12, it is known that it plays a critical role inthe regulation of the Th1 response. In these cells, interieukin 12induces the production of mainly IL-2, IFNγ, TNFα and TNFβ (Mosmann andSad, Immunol. Today 17: 138-146 (1996): Gately et al., Annu. Rev.Immunol. 16: 495-521 (1998)). Especially IFNγ is a potent mediator ofthe IL-12 action. An over-production of interferon gamma can beresponsible for, for example, the MHC II (Major HistocompatibilityComplex)-associated autoimmune diseases. (In addition, there is alsosufficient evidence with respect to a pathological role of interferongamma in allergic diseases as well as sarcoidosis and psoriasis(Billiau, A., Adv. Immunol., 62: 61-130 (1996); Basham et al. J.Immunol. 130: 1492-1494 (1983); Hu et al., Immunology, 98: 379-385(1999); Seery, J. P., Arthritis Res., 2: 437-440 (2000)). Moreover,IL-12 and L-12/IL-18-induced IFNγ from NK cells are essentially involvedin the pathomechanism of non-T-cell-mediated inflammation reactions(e.g., “Toxic Shock Syndrome,” endotoxemia, sepsis and septic shock,ARDS, “first dose response” in the case of antibody therapy, e.g., OKT3administration in the case of allografts) (Kum et al., Infect Immun. 69:7544-7549 (2001); Arad et al., J Leukoc. Biol. 69: 921-927 (2001);Hultgren et al., Arthritis Res. 3: 41-47 (2001), Arndt et al., Am. J.Respir. Cell; Mol. Biol 22: 708-713 (2000); Grohmann et al., J. Immunol.164: 4197-4203 (2000); Muraille et al., Int. Immunol. 11: 1403-1410(1999)). IL-12 also plays a role in inflammations with pathomechanismsthat are unclear at this time (e.g., eclampsia) (Hayakawa et al., J.Reprod. Immunol. 47: 121-138 (2000); Daniel et al., Am. J. Reprod.—Immunol. 39: 376-380 (1998)).

[0005] In addition to interleukin 12 and IFNγ, still other cytokines areascribed a role in the pathogenesis of immune diseases and systemicinflammation reactions, such as, for example, the TNFα. TNFα plays animportant pathological role in the case of infectious diseases (such assepsis, “toxic shock syndrome” (Tracey et al., Nature 330: 662-664(1987); Basger et al., Circ. Shock, 27: 51-61 (1989); Hinshaw et al.,Circ. Shock, 30: 279-292 (1990); Waage, A., Lancet, 351: 603 (1998);Cohen et al., Lancet, 351: 1731 (1998)), but also numerous otherimmune-mediated diseases.

[0006] For the treatment of IL 12-mediated diseases and for thereduction of acute symptoms of these diseases, corticosteroids arefrequently used, whose side effects especially in long-term treatmentoften result in a termination of treatment.

[0007] The activation of microglia represents a central step in theinflammation process of almost all degenerative diseases of the centralnervous system. The microglia can remain in the activated state over anextended period, in which they produce and secrete various inflammationfactors, e.g., reactive oxygen/nitrogen intermediate compounds,proteases, cytokines, complement factors and neurotoxins. The latter inturn produce neuronal dysfunction and degeneration. The activation ofmicroglia can be carried out by various stimuli such as, e.g.,Aβ-peptide (β-amyloid, Araujo, D. M. and Cotman, C. M., Brain Res. 569:141-145 (1992)), prion protein, cytokines or by cell fragments (Combs,C. K. et al., J. Neurosci. 19: 928-939 (1999); Wood, P. L.,Neuroinflammation: Mechanisms and Management, Humana Press (1998).

[0008] Benzimidazoles that inhibit the activation of microglia afterstimulation with the Aβ-peptide are described in WO 01/51473. From this,it is also known that benzimidazoles that inhibit the activation ofmicroglia are used for treatment of neuroinflamrnmatory diseases, suchas AIDS dementia, amyotrophic lateral sclerosis, Creutzfeldt-Jakobdisease, Down's Syndrome, diffuse Lewy Body disease, Huntington'sdisease, leukencephalopathy, multiple sclerosis, Parkinson's disease,Pick's disease, Alzheimer's disease, stroke, temporary lobe epilepsy andof tumors.

[0009] EP 0 104 727 A1 describes benzimidazole derivatives that are notsubstituted in 1-position and that have an alkyl group in 2-position.Substituents in the benzene ring of the derivatives are, i.a.,pyridyloxy, pyridylalkyl, pyridylalkyoxy and pyridyloxyalkanediylradicals.

[0010] WO 01/21634 Al also describes benzimidazole derivatives that canbe substituted in 1-position with an alkanediylamido group, in2-position with, i.a., a substituted phenyl or heteroaryl radical, andin the anellated benzene ring with, i.a., at least one substitutedalkoxy, alkylamino, alkylsulfonyl and alkylsulfoxide radical. It isindicated that these substances can be used for a considerable number ofpossible indications as active ingredients in pharmaceutical agentpreparations.

[0011] In U.S. Pat. No. 5,552,426, substituted benzimidazoles areindicated that have, i.a., a phenyl or naphthyl radical in 1-positionand, i.a., a phenyl or heterocyclic radical in 2-position. The anellatedbenzene ring of the benzimidazoles is preferably substituted with analkoxy or aminoalkoxy radical. An effectiveness against diseases thatare based on a neurotoxicity that is associated with a β-amyloid peptideis ascribed to such compounds.

[0012] WO 97/12613 A1 describes various inflammation-inhibiting andarteriosclerosis-preventing agents. For example, benzimidazolederivatives are indicated as active ingredients that are substituted in1-position with, i.a., a phenyl radical or substituted phenyl radical,and in 2-position with an alkoxy radical. Substituents in the benzenering of the active ingredient compounds can be, i.a., alkyl, nitro,halo, alkoxy, amino, ester, amide, alkanediylalkoxy and alkanediylaminoradicals.

[0013] In EP 0 520 200 A2, benzimidazole derivatives are indicated thathave aryl radicals that are substituted in 1-position and amino groupsthat are monosubstituted or disubstituted in 2-position or areunsubstituted. The benzene ring of the benzimidazole skeleton can besubstituted with halogen, trifluoromethyl and/or cyano. These compoundsare used for treating diseases that are associated with an increasedactivation of Ca-channels.

[0014] In WO 97/33873 A1, benzimidazole derivatives are also indicatedthat are used for treating cystitis. In 1-position, these compounds canhave, i.a., phenyl, naphthyl and unsaturated heterocyclic radicals. In2-position, the derivatives can be substituted with alkoxy,phenylalkoxy, naphthylalkoxy, heterocyclic alkoxy or unsaturatedheterocylic alkoxy radicals. The benzene ring of the skeleton of thederivatives can be substituted with nitro, alkanoyl, amino, alkyl,alkoxy, cycloalkyl, heterocyclic, unsaturated heterocyclic, halo,alkylthio, hydroxyalkylidenyl, hydroxyalkylidenylamino,aminoalkylidenyl, aminoalkoxy, hydroxyalkyl, heterocyclic alkoxy,aminoalkylidenyl or trifluoromethyl radicals.

[0015] In EP 0 531 883 A1, condensed 5-membered heterocycles areindicated, for example substituted benzimidazole derivatives, wherebythese compounds, according to the general description of the compounds,are preferably substituted with a substituted alkyl radical in1-position and, for example, with an O-alkanediyl, S-alkanediyl,NH-alkanediyl, N(alkyl)-alkanediyl, SO-alkanediyl or SO₂-alkanediylradical in 2-position. The described compounds are to have anantithrombic action.

[0016] For a possible therapy of neuroinflanunation, to datenon-steroidal inflammation inhibitors (COX II inhibitors) [McGeer, P.L., Roger, Neurology, 42, 447-449 (1992), Rogers, J.; Kirby, L. C.;Hempleman, S. R.; Berry, D. L.; McGeer, P. L.; Kaszniak, A. W.;Zalinski, J.; Cofield, M.; Mansukhani, L.; Wilson, P.; Kogan, F.,Neurology, 43, 1609-1611 (1993), Andersen, K.; Launer, L. J.; Ott, A.;Hoes, A. W.; Breteler, M. M. B.; Hoftnan, A., Neurology, 45, 1441-1445(1995), Breitner, J. C. S.; Gau, B. A.; Welsh, K. A.; Plassman, B. L.;McDonald, W. M.; Helms, M. J.; Anthony, J. C., Neurology, 44 227-232(1994), The Canadian Study of Health and Aging, Neurology, 44, 2073-2079(1994)], Cytokine Modulators [McGeer, P. L.; McGeer, E. G., Brain Res.Rev., 21: 195-218 (1995), McGeer, E. G.; McGeer, P. L., CNS Drugs, 7,214-228 (1997), Barone, F. C. and Feuerstein, G. Z., J. Cerebral BloodFlow and Metabolism, 19, 819-834 (1999)] and complementary cascadeinhibitors [Chen, S., Frederickson, R. C. A., and Brunden, K. R.,Neurobiol. Aging (1996), McGeer, E. G.; McGeer, P. L., Drugs, 55:739-746 (1998)] have been described.

[0017] The compounds that are known for treating immunological diseases,such as, e.g., steroids, frequently act on several factors in the immunesystem and thus trigger numerous side effects. The object is thereforeto make available substances that inhibit the cytokine activity based ontheir microglia activity without triggering serious toxic side effects.

[0018] The problem is solved by novel benzimidazole derivativesaccording to claim 1, in addition by the use of a benzimidazolederivative according to the invention for the production of apharmaceutical agent for interrupting the IL 12 and INFγ production incells of monocytic origin or T cells and NK cells.

[0019] Based on their ability to interrupt the production of 1L 12 andTNFα in monocytes/macrophages/dendrites and the IFNγ production in Tcells and NK cells, microglia inhibitors are suitable for treatingnumerous diseases that are triggered by the increased production ofcytokines, such as, e.g., TNFα, β, IFNγ, IL-2 and IL 12, such asinflammatory diseases that are not based on neuroinflammation,autoimmune diseases, allergic and infectious diseases, toxin-inducedinflammations, pharmacologically triggered inflammation reactions aswell as pathophysiologically relevant inflammation reactions of anorigin that is unclear at this time.

[0020] The benzimidazole derivatives according to the invention have thefollowing general structural formula I:

[0021] Here:

[0022] R¹ is a phenyl group that is optionally substituted with up tothree of the following substituents, independently of one another:

[0023] F, Cl, Br, I

[0024] OH, OR⁴, OCOR⁴

[0025] SR⁴, SOR⁴, SO₂R⁴,

[0026] R⁴,

[0027] NH², NHR⁴, NR⁴R^(4′)

[0028] or two adjacent substituents at R¹ together form an —O—CH₂—O—,—O—CH₂—CH₂—O— or —CH₂—CH₂—CH₂ group,

[0029] R² is a monocyclic or bicyclic 5- to 10-membered heteroaryl groupwith 1-2 heteroatoms, selected from N, S and O, which optionally issubstituted with up to two of the following substituents, independentlyof one another:

[0030] F, Cl, Br, I

[0031] OH, OR⁴, OCOR⁴,

[0032] COR⁴

[0033] SR⁴, SOR⁴, SO₂R⁴,

[0034] R⁴,

[0035] or two adjacent substituents at R² together form an —O—CH₂—O—,—O—CH₂—CH₂—O— or —CH₂—CH₂—CH₂— group,

[0036] R³ is H, OH or O—C₁₋₆-alkyl,

[0037] R⁴ and R⁴′, independently of one another, are C₁₋₄-perfluoroalkylor C₁₋₆-alkyl,

[0038] A is a C₂₋₆-alkylene group, which optionally is substituted with═O, OH, O—C₁₋₃-alkyl, NH₂, NH—C₁₋₃-alkyl, NH—C₁₋₃-alkanoyl,N(C₁₋₃-alkyl)₂, and N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl),

[0039] B is COOH, CONH₂, CONHNH₂, CONHR⁵, CONR⁵R^(5′), in each casebonded to a carbon atom of group A,

[0040] R⁵ and R^(5′), independently of one another, are in each case aradical, selected from the group that comprises C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkinyl, whereby a C atom can be exchanged for O, S,SO, SO₂, NH, N—C₁₋₃-alkyl or N—C₁₋₃-alkanoyl, and also(C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl), whereby in a five-membered cycloalkylring, a ring member can be ring N or ring 0, and in a six- orseven-membered cycloalkyl ring, one or two ring members in each case canbe ring-N atoms and/or ring-O atoms, whereby the ring-N atoms optionallycan be substituted with C₁₋₃-alkyl or C₁₋₃-alkanoyl, as well as also(C₀₋₃-alkanediyl-phenyl) and (C₀₋₃-alkanediyl-heteroaryl);

[0041] whereby the heteroaryl group is five- or six-membered andcontains one or two heteroatoms that are selected from the group thatcomprises N, S and O,

[0042] whereby all above-mentioned alkyl and cycloalkyl radicalsoptionally can be substituted with up to two radicals that are selectedfrom the group that comprises CF₃, C₂F₅, OH, O—C₁₋₃-alkyl, NH₂,NH—C₁₋₃-alkyl, NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂,N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), COOH, CONH₂ and COO—C₁₋₃-alkyl, and allabove-mentioned phenyl and heteroaryl groups optionally can besubstituted with up to two radicals that are selected from the groupthat comprises F, Cl, Br, CH₃, C₂H₅, OH, OCH₃, OC₂H₅, NO₂, N(CH₃)₂, CF₃,C₂F₅ and SO₂NH¹

[0043] or R⁵ and R⁵ together with the N atom form a five- toseven-membered heterocyclic ring that can contain another N or O or Satom and that can be substituted with C₁₋₄-alkyl,(C₀₋₂-alkanediyl-C₁₋₄-alkoxy), C₁₋₄-alkoxycarbonyl, aminocarbonyl orphenyl

[0044] as well as their optical or geometric isomers or tautomeric formsor pharmaceutically applicable salts,

[0045] whereby the following compounds are ruled out:

[0046] 6-[[1-Phenyl-2-(pyridin-4-yl)-1H-benzimidazol-6-yl]oxy]hexanoicacid,

[0047]6-[[1-phenyl-2-(benzothien-2-yl)-1H-benzimidazol-6-yl]oxy]hexanoic acid.

[0048] Preferred are compounds in which

[0049] R¹ is a phenyl group, which optionally is substituted with up totwo of the following substituents, independently of one another:

[0050] F, Cl,

[0051] OH, OR⁴, OCOR⁴

[0052] SR⁴,

[0053] R⁴ or

[0054] two adjacent substituents at R¹ form an —O—CH₂—O— or—CH₂—CH₂—CH₂-group.

[0055] Preferred are also benzimidazole derivatives, in which

[0056] R² is a monocyclic 5- to 6-membered heteroaryl group with 1-2heteroatoms, selected from the group that comprises N, S and O, whichoptionally is independently substituted with up to two of the followingsubstituents:

[0057] F, Cl,

[0058] OR⁴, OCOR⁴

[0059] SR⁴, SOR⁴, SO₂R⁴,

[0060] R⁴ or

[0061] two adjacent substituents at R² form an —O—CH₂—O— or—CH₂—CH₂—CH₂-group.

[0062] Preferred are also benzimidazole derivatives in which

[0063] R³ is H.

[0064] Preferred are also benzimidazole derivatives in which

[0065] R⁴ and R^(4′), independently of one another, are C₁₋₂perfluoroalkyl, and C₁₋₄ alkyl.

[0066] Preferred are also benzimidazole derivatives in which

[0067] R⁵ and R^(5′), independently of one another, are C₁₋₆ alkyl,whereby a carbon atom can be exchanged for O, S, SO, SO², C₃₋₅cycloalkyl-C₀₋₃ alkylene, whereby in a 5-membered cycloalkyl ring, aring member can be an N or an O, whereby the ring nitrogen optionally issubstituted with C₁₋₃ alkyl or C₁₋₃ alkanoyl,

[0068] C₀₋₂ alkylene-(5- to 6-membered heteroaryl with 1-2 heteroatomsfrom N, S and O)

[0069] whereby all above-mentioned alkyl and cycloalkyl radicals can besubstituted with CF₃, OH, NH2, NH C₁₋₃ alkyl, NH C₁₋₃ alkanoyl,N(C₁₋₃alkyl)₂, N(C₁₋₃ alkyl)(C₁₋₃ alkanoyl), COOH, CONH₂ and allabove-mentioned heteroaryl groups with one or two substituents from thegroup that consists of F, Cl, CH₃, C₂H₅, OCH₃, OC₂H₅, CF₃, C₂F₅,

[0070] or R⁵ and R^(5′) together with the nitrogen atom form a 5- to7-membered heterocyclic compound, which can contain another oxygen,nitrogen or sulfur atom and can be substituted with C₁₋₄-alkyl orC₁₋₄-alkoxy-C₀₋₂-alkyl.

[0071] Preferred are benzimidazole derivatives in which

[0072] A is a straight-chain C₃₋₆-alkylene.

[0073] Preferred are benzimidazole derivatives in which

[0074] B is COOH or CONH₂

[0075] in each case bonded to a carbon atom of group A.

[0076] Especially preferred are the following benzimidazoles:

[0077]6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid

[0078]5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid

[0079] 4-[[L-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyric acid

[0080]6-[[1-(4-methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid

[0081]6-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid

[0082]5-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid

[0083]4-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyricacid

[0084] 5-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid

[0085] 4-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyric acid

[0086] 6-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid

[0087]6-[[1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid

[0088]5-[[1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid

[0089]6-[[1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid

[0090]5-[[1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid

[0091] 5-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid

[0092] 4-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyricacid

[0093] 6-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid

[0094]N-(3-methoxypropyl)-6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0095]6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]-1-morpholin-1-ylhexan-1-one

[0096]N-methyl-6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0097]N,N-dimethyl-6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0098]6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0099]N-cyclopropyl-6-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0100]N-methyl-6-[[1-(4-methylphenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0101]6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]-1-(thiazolidin-3-yl)-hexan-1-one

[0102]N-(2-methoxyethyl)-5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamide

[0103]N,N-dimethyl-5-[[1-(4-methyphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]-pentanamide

[0104]5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamide6-[[1-(4-methylphenyl)-2-(2-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid.

[0105] This invention comprises the physiologically compatible salts ofthe above-mentioned compounds, especially the acid salts of the nitrogenbases of the benzimidazole derivatives according to the invention, alsothe salts of carboxylic acids of the derivatives according to theinvention with bases.

[0106] The benzimidazole derivatives according to the invention can haveone or more asymmetric centers, such that the compounds can occur inseveral isomeric forms. The compounds of formula I can also be presentas tautomers, stereoisomers or geometric isomers. The invention alsocomprises all possible isomers, such as E- and Z-isomers, S- andR-enantiomers, diastereomers, racemates and mixtures thereof includingthe tautomeric compounds. All of these isomeric compounds are—even ifnot expressly indicated otherwise in each case—components of thisinvention.

[0107] The isomer mixtures can be separated into enantiomers orE/Z-isomers according to commonly used methods, such as, for examplecrystallization, chromatography or salt formation.

[0108] The heteroaryl groups that are contained in the benzimidazolecompounds according to the invention are built up of five or tenskeleton atoms and can contain one or two heteroatoms. Heteroatoms areoxygen (O), nitrogen (N) and sulfur (S).

[0109] Examples of monocyclic heteroaryl groups are pyrrolyl, thienyl,furanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.

[0110] Examples of a bicyclic heteroaryl group are indolyl, isoindolyl,benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, quinolyl,isoquinolyl, phthalazinyl, quinazolinyl, cinnolinyl, quinoxalinyl andnaphthyridinyl. If the heteroaryl group is part of R¹, the binding to Nof the benzimidazole is carried out via a carbon atom.

[0111] Heteroaryl radicals can be bonded in any way to the benzimidazoleskeleton or another group, for example as 2-, 3- or 4-pyridinyl, as 2-or 3-thienyl or as 1-imidazolyl.

[0112] Alkyl groups can be straight-chain or branched. Examples of alkylgroups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, n-hexyl, andsec-hexyl.

[0113] Perfluorinated alkyls are preferably CF₃ and C₂F₅ Cycloalkylgroups are preferably defined in each case as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

[0114] Mentioned as a saturated heterocyclic ring or as a cycloalkylwith one or more heteroatoms are, for example: piperidine, pyrrolidine,tetrahydrofuran, morpholine, piperazine, hexahydroazepine as well as2,6-dimethyl-morpholine, N-phenyl-piperazine,2-methoxymethyl-pyrrolidine, piperidine-4-carbonamide, thiomorpholineand thiazolidine, whereby the linkage can be carried out via optionallypresent ring-N atoms.

[0115] As straight-chain or branched alkylene for A with up to six Catoms, there can be mentioned, for example: ethylene, propylene,butylene, pentylene, hexylene, also 1-methylethylene, 1-ethylethylene,1-methylpropylene, 2-methylpropylene, 1-methyl-butylene,2-methylbutylene, 1-ethylbutylene, 2-ethylbutylene, 1-methylpentylene,2-methylpentylene, 3-methylpentylene as well as analogous compounds.

[0116] A can be substituted in two places, preferably in one place, withOH, NH₂, NH—C₁₋₃-alkyl or NH—C₁₋₃-alkanoyl.

[0117] The physiologically compatible acid salts of the nitrogen basesof the benzimidazole derivatives according to the invention can beformed with inorganic and organic acids, for example with oxalic acid,lactic acid, citric acid, fumaric acid, acetic acid, maleic acid,tartaric acid, phosphoric acid, hydrochloric acid, hydrobromic acid,sulfuric acid, p-toluenesulfonic acid and methanesulfonic acid.

[0118] For salt formation of acid groups, especially carboxylic acidgroups, the inorganic or organic bases that are known for formingphysiologically compatible salts, such as, for example, alkalihydroxides, especially sodium hydroxide and potassium hydroxide,alkaline-earth hydroxides, such as calcium hydroxide, also ammonia, aswell as amines, such as ethanolamine, diethanolamine, triethanolamine,N-methylglucamine and tris-(hydroxymethyl)-methylamine, are alsosuitable.

[0119] The compounds of formula I inhibit the activation of themicroglia and the production of interleukin 12 (IL 12) and interferon y(IFNγ). The invention therefore also relates to the use of a compound offormula I, as well as optical or geometric isomers thereof or tautomersthereof or physiologically compatible salts for the production of apharmaceutical agent for treating or preventing a disease that isassociated with a microglia activation, especially a disease that istriggered by the overproduction of IL 12 and IFNγ and for induction ofinterleukin 10 (IL-10).

[0120] In a preferred embodiment, the compounds according to theinvention are used for treating a T-cell-mediated, especially aTh1-cell-mediated immunological disease and non-T-cell-mediatedinflammation reactions. In particular, the compounds according to theinvention are used for the production of a pharmaceutical agent forinterrupting the IL 12 and IFNγ production in cells of monocytic originor T cells and NK cells. Based on their ability to interrupt theproduction of IL 12 and TNFα in monocytes/macrophages and the IFNγproduction in T cells, the compounds according to the invention aresuitable for treating numerous diseases that are triggered by theincreased production of cytokines, such as, e.g., TNFα, β, IFNγ, IL 2and IL 12, such as inflammatory diseases that are not based onneuroinflammation, autoimmune diseases, allergic and infectiousdiseases, toxin-induced inflammations, pharmacologically triggeredinflammation reactions as well as pathophysiologically relevantinflammation reactions of an origin that is unclear at this time.

[0121] Examples of inflammatory and autoimmune diseases are: chronicinflammatory intestinal diseases (inflammatory bowel diseases, Crohn'sdisease, ulcerative colitis), arthritis, allergic contact dermatitis,psoriasis, pemphigus, asthma, multiple sclerosis, diabetes, type-1insulin-dependent diabetes mellitus, rheumatoid arthritis, lupusdiseases and other collagenoses, Graves' disease, Hashimoto's disease,“graft-versus-host disease” and transplant rejection.

[0122] Examples of allergic, infectious and toxin-triggered andischemia-triggered diseases are: sarcoidosis, asthma, hypersensitivepneumonitis, sepsis, septic shock, endotoxin shock, toxic shocksyndrome, toxic liver failure, ARDS (acute respiratory, distresssyndrome), eclampsia, cachexia, acute virus infections (e.g.,mononucleosis, fulminating hepatitis), and post-reperfusion organdamage.

[0123] An example of a pharmacologically triggered inflammation withpathophysiological relevance is the “first dose response” after theadministration of anti-T-cell antibodies such as OKT3.

[0124] An example of systemic inflammation reactions of an origin thatis unclear at this time is eclampsia.

[0125] Examples of neuroinflammatory diseases that are associated with amicroglia activation are AIDS dementia, amyotrophic lateral sclerosis,Creutzfeldt-Jakob disease, Down's Syndrome, diffuse Lewy Body disease,Huntington's disease, leukencephalopathy, multiple sclerosis,Parkinson's disease, Pick's disease, Alzheimer's disease, stroke,temporary lobe epilepsy and tumors. The invention therefore also relatesto the use of the indicated benzimidazole derivatives for treating thesediseases as well as for preventing these diseases.

[0126] Compounds that with stimulation with the Aβ-peptide achieve aninhibition of the microglia activity of at least 20% and an inhibitionof the cytokine activity of at least 30% are suitable, according to theinvention, as microglia inhibitors. The biological properties of themicroglia inhibitors can be shown according to the methods that areknown to one skilled in the art, for example with the aid of the testingmethods that are described below and in WO 01/51473.

[0127] Example 29 describes how the inhibition of the microgliaactivation can be measured. In this case, the microglia can be activatedby various stimuli such as, for example, with Aβ-peptide [β-amyloid,Araujo, D. M. and Cotman, C. M., Brain Res. 569: 141-145 (1992)], withprion protein, cytokines or by cell fragments [Combs, C. K. et al., JNeurosci. 19: 928-939, (1999); Wood, P. L., Neuroinflammation:Mechanisms and Management, Humana Press, (1998)].

[0128] The stimulation with the Aβ-peptide corresponds to thepathophysiological situation in the case of Alzheimer's disease. In thistest, the substances according to the invention in the case ofstimulation with the Aβ-peptide showed an inhibition of the microgliaactivation. The inhibition of the microglia activation by the substancesaccording to the invention results in a strong reduction of the cytokineproduction and cytokine secretion, for example of II1β and TNFα((measured by ELISA and mRNA expression analysis), and in a reducedsecretion of reactive oxygen/nitrogen intermediate compounds. Severalinflammation factors are thus equally inhibited.

[0129] The in vivo action of the substances according to the inventionwas shown in an MCAO model in rats. This model simulates the conditionof a stroke. The substances according to the invention reduce themicroglia activation, whioh occurs in the case of acute brain lesions inthe brains of animals.

[0130] The inhibition of cytokine production is produced, for example,by measuring TNFα and interleukin 12 in lipopolysaccharide(LPS)-stimulated THP-1 cells.

[0131] The compounds according to the invention inhibit the TNFα andinterleukin 12 production in lipopolysaccharide (LPS)-stimulated THP-1cells. To visualize the influence of substances on the T-cellactivation, for example, the measurement of the INFγ secretion is used.The compounds according to the invention inhibit the INFy production ofperipheral mononuclear blood cells.

[0132] The invention also relates to pharmaceutical agents that containone or more compounds of general formula I according to the invention aswell as one or more vehicles. The pharmaceutical agents or compositionsof the invention are produced with commonly used solid or liquidvehicles or diluents and commonly used pharmaceutical and technicaladjuvants according to the desired method of administration with asuitable dosage in a way that is known in the art. Preferredpreparations consist in a dispensing form that is suitable for oral,enteral or parenteral administration, for example i.p.(intraperitoneal), i.v. (intravenous), i. m. (intramuscular) orpercutaneous administration. Such dispensing forms are, for example,tablets, film tablets, coated tablets, pills, capsules, powders, creams,ointments, lotions, liquids, such as syrups, gels, injectable liquids,for example for i.p., i.v., i.m. or percutaneous injection, etc. Inaddition, depot forms such as implantable preparations, as well assuppositories, are also suitable. In this case, depending on their type,the individual preparations release to the body the derivativesaccording to the invention gradually or all at once in a short time.

[0133] For oral administration, capsules, pills, tablets, coated tabletsand liquids or other known oral forms for dispensing can be used aspharmaceutical preparations. In this case, the pharmaceutical agents canbe formulated in the way that they release the active ingredients eitherin a short time and pass on to the body or have a depot action, so thata longer-lasting, slow supply of active ingredients to the body isachieved. In addition to at least one benzimidazole derivative, thedosage units can contain one or more pharmaceutically compatiblevehicles, for example substances for adjusting the rheology of thepharmaceutical agent, surfactants, solubilizers, microcapsules,microparticles, granulates, diluents, binders, such as starches, sugar,sorbitol and gelatins, also fillers, such as silicic acid and talc,lubricants, dyes, perfumes and other substances.

[0134] Corresponding tablets can be obtained by, for example, mixing anactive ingredient with known adjuvants, for example inert diluents suchas dextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone,explosives such as corn starch or alginic acid, binders such as starchor gelatin, lubricants such as carboxypolymethylene, carboxy methylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tabletscan also consist of several layers.

[0135] Coated tablets can be produced accordingly by coating cores thatare produced analogously to the tablets with agents that are commonlyused in tablet coatings, for example polyvinyl pyrrolidone or shellac,gum arabic, talc, titanium oxide or sugar. In this case, the shell ofthe coated tablet can also consist of several layers, whereby theadjuvants that are mentioned above in the case of the tablets can beused.

[0136] Capsules that contain active ingredients can be produced, forexample, by the active ingredient being mixed with an inert vehicle suchas lactose or sorbitol and encapsulated in gelatin capsules.

[0137] The benzimidazole derivatives according to the invention can alsobe formulated in the form of a solution that is intended for oraladministration and that in addition to the active benzimidazolederivative contains as components a pharmaceutically compatible oiland/or a pharmaceutically compatible lipophilic surfactant and/or apharmaceutically compatible hydrophilic surfactant and/or apharmaceutically compatible water-miscible solvent.

[0138] To achieve better bio-availability of the active ingredientsaccording to the invention, the compounds can also be formulated ascyclodextrin clathrates. To this end, the compounds are reacted with α-,β- or γ-cyclodextrin or derivatives thereof.

[0139] If creams, ointments, lotions and liquids that can be appliedtopically are to be used, the latter must be constituted so that thecompounds according to the invention are fed to the body in adequateamounts. In these forms for dispensing, adjuvants are contained, forexample substances for adjusting the rheology of pharmaceutical agents,surfactants, preservatives, solubilizers, diluents, substances forincreasing the permeability of the benzimidazole derivatives accordingto the invention through the skin, dyes, perfumes and skin protectionagents, such as conditioners and moisturizers. Together with thecompounds according to the invention, other active ingredients can alsobe contained in the pharmaceutical agent [Ullmanns Enzyklopädie dertechnischen Chemie [Ullmann 's Encyclopedia of Technical Chemistry],Volume 4 (1953), pages 1-39; J. Pharm. Sci., 52, 918 ff. (1963); issuedby Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete[Adjuvants for Pharmaceutics and Related Fields], Pharm. Ind., 2, 72ff(1961); Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie,Kosmetik und angrenzende Gebiete [Dictionary ofAdjuvants forPharmaceutics, Cosmetics and Related Fields], Cantor A G,Aulendorf/Württ., 1971].

[0140] The substances according to the invention can also be used insuitable solutions such as, for example, physiological common saltsolution, as infusion or injection solutions. For parenteraladministration, the active ingredients can be dissolved or suspended ina physiologically compatible diluent. As diluents, in particular oilysolutions, such as, for example, solutions in sesame oil, castor oil andcottonseed oil, are suitable. To increase solubility, solubilizers, suchas, for example, benzyl benzoate or benzyl alcohol, can be added.

[0141] To formulate an injectable preparation, any liquid vehicle can beused in which the compounds according to the invention are dissolved oremulsified. These liquids frequently also contain substances forregulating viscosity, surfactants, preservatives, solubilizers, diluentsand other additives, with which the solution is set to isotonic. Otheractive ingredients can also be administered together with thebenzimidazole derivatives.

[0142] It is also possible to incorporate the substances according tothe invention in a transdermal system and thus to administer themtransdermally. To this end, the benzimidazole derivatives are applied inthe form of a depot injection or an implant preparation, for examplesubcutaneously. Such preparations can be formulated in such a way that adelayed release of active ingredients is made possible. To this end,known techniques can be used, for example depots that dissolve oroperate with a membrane. Implants can contain as inert materials, forexample, biodegradable polymers or synthetic silicones, for examplesilicone gum. The benzimidazole derivatives can also be incorporated in,for example, a patch, for percutaneous administration.

[0143] The dosage of the substances of general formula I according tothe invention is determined by the attending physician and depends on,i.a., the substance that is administered, the method of administration,the disease that is to be treated and the severity of the disease. Thedaily dose is no more than 1000 mg, preferably no more than 100 mg,whereby the dose can be given as a single dose to be administered onceor divided into two or more daily doses.

[0144] The benzimidazoles of formula I are accessible in various waysaccording to processes that are known in the literature per se.

[0145] As possible processes in addition to others, the following can bementioned:

[0146] 1. By reaction of ortho-leaving group-subsituted (preferablyhalogen-substituted) nitrobenzene derivatives (A) with arylamines (B),N-aryl-2-nitrobenzenes (C) can be produced under diverse reactionconditions, such as, for example, by heating reactants with or without asuitable inert solvent, such as, e.g., alkylbenzenes. Also, the aminethat is used as a reactant can be used in excess as a solvent. Thereactions are carried out both with and without bases (for example,potassium carbonate, sodium hydride). Other adjuvants, such as, e.g.,copper salts, can also be used. Examples of the procedures that areindicated here are found in numerous works, such as, for example, in: D.Jerchel, H. Fischer, M. Graft, Ann. Chem., 575, 162 (1952) CAS, 53(2138); R.-A. Abramovitch, Can. J Chem., 38, 2273, 1960).

[0147] Abgangsgruppe Leaving group

[0148] Substituent(en) oder H=Substituent(s) or H

[0149] The thus obtained N-arylnitroaniline derivatives (C) can beconverted in various ways into 1,2-disubstituted benzimidazoles (E):

[0150] The reduction of nitro group (C) is carried out preferably byhydrogenation in polar solvents such as acetic acid, lower alcohols orethyl acetates with the addition of catalysts, such as Raney nickel orpalladium on carbon, or by chemical reduction with, for example, tin inhydrochloric acid, SnCl₂ [F. D. Bellamy, Tet. Lett., (1984)] orFe/acetic acid [D.C. Owsily, J. J. Bloomfield, Synthesis, 118, 150(1977)].

[0151] From the diamines (D), benzimidazoles (E) can be obtained byreaction with acid derivatives, such as orthoesters, iminoesters, acidanhydrides, aldehydes or else free carboxylic acids with or withoutacidic catalysis and/or dehydrating agents. As an example, here, theproduction of 1,2-diphenylbenzimidazole from benzoic acid andN-phenyl-o-phenylenediamine with use of triphenyl phosphine oxide andtrifluoromethanesulfonic acid anhydride can be cited [J. B. Hendrickson,M. S. Hussoin, J. Org. Chem., 52, 4137 (1987)].

[0152] When using aromatic aldehydes, for example, nitrobenzene is usedas a solvent to be able to perform in situ the oxidation of the primaryformed benzimidazoline. Also, the cyclization to benzimidazoles isaccomplished by aromatic aldehydes being reacted as bisulfite adductswith diamines (D).

[0153] 2. T. Benincori and F. Sannicolo in J. Heterocyclic Chem. 25,1029 (1988) describe another access to benzimidazoles (E) that makespossible a broad variation of the substitution pattern both of the twoaryl substituents and on the benzene ring of the benzimidazole. For oneskilled in the art, it is obvious that these substituents must becompatible with the reactants and reaction conditions that are used inthe course of the synthesis sequence. Sometimes, the substituents can bemodified later. Here in the product, a hydroxy group is always containedin 6-position of the benzimidazole (cef. structure F).

[0154] 3. Finally, it can be mentioned that in some cases, thepossibility exists of direct N-arylation of pre-fabricatedbenzimidazoles, e.g., according to M. J. Sansone; M. S. Kwiatek, U.S.Pat. No. 4,933,397, or D. M. T. Chan; K. L. Monaco; R.-P. Wang; M. P.Winters, Tet. Lett. 39 (1998) 2933 orA. P. Combs, S. Saubem, M.Rafalski, P. Y. S. Lam, Tet. Lett. 40 (1999) 1623.

[0155] It is obvious to one skilled in the art that substituents R mustbe compatible with the reagents and reaction conditions that are used inthe course of the synthesis sequence. The substituents optionally can bemodified later.

[0156] If structural element B-A-O (formula I) is established inprotected or unprotected form because of incompatibility with thereaction conditions during the respective benzimidazole synthesis or forother synthetic reasons only after benzimidazole synthesis has beenconcluded, various procedures, depending on substituents R³ that areentrained in the benzene ring of the benzimidazole, are possible forestablishing the B-A-O structural element (formula I), whereby, as isobvious to one skilled in the art, a compatibility of the methods usedwith aryl substituents and other radicals R³ must be considered.

[0157] Below are some possibilities for establishing the B-A-Ostructural element:

[0158] Oxygen can be entrained from the start in free form (e.g., R═OHin formula (A)) or else in protected form, for example as alkyl ether[cf., for example: B. D. Jerchel, H. Fischer, M. Graft, Ann. Chem., 575,162 (1952)] as a substituent in a benzimidazole synthesis. By alkylether cleavage, with, e.g., concentrated hydrobromic acid with theoptional aid of solubilizers such as halogenated hydrocarbons or elsewith boron tribromide in inert solvents, such as, for example,dichloromethane, the hydroxyl group can be released. The hydroxyl groupcan be reacted according to known methods with optionally one terminalgroup B (Formula I) or alkyl halides that contain a precursor thereof toform the ethers, whereby the reaction is carried out with the alkylatingagents preferably in polar solvents, such as, for example,dimethylformamide, dimethyl sulfoxide, ethers, such as, for example,tetrahydrofuran or else lower ketones, such as acetone or methylethylketone, with the addition of bases, such as alkali and alkaline-earthhydrides, but preferably sodium hydride, or with the addition of alkalicarbonates, such as potassium or cesium carbonate, at a temperaturerange of 0° C. to 120° C. In addition, a reaction can be carried out ina two-phase system with phase transfer catalysis, whereby the reactantsare dissolved in a suitable inert organic solvent, such as, for example,in haloalkanes, but preferably in dichloromethane. The other phase is asolid alkali hydroxide, preferably sodium or potassium hydroxide, orelse a concentrated aqueous solution of the hydroxide in question. Asphase transfer catalysts, for example, quaternary ammonium salts areused. Reactions under phase transfer catalysis are preferably carriedout at room temperature.

[0159] For example, a compound of formula A (with R═OH) is dissolved indimethylformamide and reacted with the addition of cesium carbonate with6-bromohexanoic acid methyl ester at temperatures of 0° C. to 50° C. Thecleavage of the ester by acidic or alkaline hydrolysis can be carriedout according to methods that are known to one skilled in the art, suchas, for example, with basic catalysts, such as, for example, with alkalior alkaline-earth carbonates or hydroxides in water or the aqueoussolution of an alcohol. As alcohols, aliphatic alcohols, such as, forexample, methanol, ethanol, butanol, etc., are considered, butpreferably methanol. Aqueous solutions of ethers, such astetrahydrofuran, are also used. As alkali carbonates and alkalihydroxides, lithium, sodium and potassium salts can be mentioned.Preferred are the lithium and sodium salts. As alkaline-earth carbonatesand hydroxides, for example, calcium carbonate, calcium hydroxide andbarium carbonate are suitable. The reaction is generally carried out at−10° C. to 70° C., but preferably at 25° C. The ester cleavage can alsobe carried out, however, under acidic conditions, such as, for example,in aqueous hydrochloric acid, optionally with the aid of a solubilizer,such as, for example, a lower alcohol, preferably methanol.

[0160] From a nitrile that is present in the alkylating reagent or elsegenerated later, a carboxylic acid group can be generated by hydrolysis.The alkylating reagents can also contain functional groups such as, forexample, hydroxyl groups in free or protected form, which can beexchanged after conversion into leaving groups, such as, for example,tosylate, mesylate, bromide or iodide, for example, for amino or alkylgroups. Also, the alkylating reagents can contain functional groups,such as, for example, halogens or optionally protected amino groups,which can then be further modified.

[0161] Depending on the substitution desired, substituents R³ arecontained in the synthesis components from the start or are establishedif necessary at suitable sites of the synthesis sequence in question orare generated from suitable precursors that are entrained.

[0162] The free acid derivatives of Formula I or ester precursors can beconverted according to diverse processes that are known in theliterature into amide derivatives of Formula I.

[0163] The free acid derivatives of Formula I can also be converted withneutralization to salts with suitable amounts of the correspondinginorganic bases. For example, when the corresponding acids are dissolvedin water, which contains stoichiometric amounts of the base, the solidsalt is obtained after the water is evaporated or after a water-misciblesolvent, for example alcohol or acetone, is added.

[0164] The amine salts can be produced in the usual way. To this end,the corresponding acid is dissolved in a suitable solvent, such as, forexample, ethanol, acetone, diethyl ether or benzene, and one to fiveequivalents of the respective amine is added to this solution. In thiscase, the salt usually accumulates in solid form or is isolated afterthe solvent is evaporated in the usual way.

[0165] The clathrates with α-, β- or γ-cyclodextrin are obtainedanalogously to the instructions in WO-A-87/05294. β-Cyclodextrin ispreferably used. Liposomes are produced according to the process that isdescribed in Pharmazie in unserer Zeit [Pharmaceutics in Our Time], 11,98 (1982).

[0166] Below, the production of several precursors, intermediateproducts and products is described by way of example. If the productionof the starting compounds is not described, the starting compounds areknown and commercially available, or the compounds are synthesizedanalogously to the described processes.

[0167] In the production of the substances according to the invention,for example, the following processes are used:

[0168] General Operating Instructions 1:

[0169] Reduction of Nitro Groups

[0170] The compound that is to be reduced is dissolved in ethyl acetate,tetrahydrofuran, methanol or ethanol or mixtures of the solvent, and itis hydrogenated to 2 to 5% (relative to the nitro compound) palladium oncarbon (10%) at normal pressure. After hydrogen absorption has ended, itis suctioned off, the residue is washed with ethyl acetate or methanolor ethanol, and the filtrate is concentrated by evaporation in a vacuum.The crude product is reacted generally without further purification.

[0171] General Operating Instructions 2:

[0172] Ether Cleavage with Hydrobromic Acid

[0173] 5 g of arylmethyl ether is mixed with 160 ml of 48% aqueous HBrand refluxed for 1-5 hours. After cooling, it is filtered. The residueis taken up in ethyl acetate and extracted three times with saturatedsodium bicarbonate solution. After drying on sodium sulfate, it isconcentrated by evaporation in a vacuum. If necessary, the residue ispurified on silica gel by crystallization or column chromatography.

[0174] General Operating Instructions 3:

[0175] Alkylation of Hydroxybenzimidazole Derivatives and PhenolDerivatives with Alkyl Halides

[0176] A solution of 1.85 mmol of the hydroxybenzimidazole derivative in12 ml of N,N-dimethylformamide is mixed with 1.85 mmol of cesiumcarbonate and 2.24 mmol of alkyl bromide or alkyl iodide. When alkylbromides are used, 1.85 mmol of sodium iodide is optionally added. It isstirred for 12 to 96 hours, then poured onto water, taken up with ethylacetate, the organic phase is washed four times with water, dried onsodium sulfate and concentrated by evaporation in a vacuum.

[0177] As an alternative to this aqueous working-up, the reactionmixture can be mixed with dichloromethane, separated from theprecipitating salts by filtration and the filtrate concentrated byevaporation in a vacuum.

[0178] Independently of the working-up method, the residue is purifiedby crystallization or column chromatography on silica gel.

[0179] General Operating Instructions 4:

[0180] Saponification of Carboxylic Acid Alkyl Esters

[0181] 0.77 mmol of the carboxylic acid alkyl ester is dissolved in 5 mlof methanol and 5 ml of tetrahydrofuran, and it is mixed with 5 ml of a0.5N aqueous lithium or sodium hydroxide solution. After 2 to 12 hoursof stirring, it is concentrated by evaporation in a vacuum to a verylarge extent, neutralized by the addition of aqueous hydrochloric acidand extracted with ethyl acetate. It is dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified, ifnecessary, by column chromatography on silica gel.

[0182] General Operating Instructions 5:

[0183] Cyclization to Benzimidazoles with Aldehydes

[0184] 1 mmol of a 1,2-diaminobenzene derivative is dissolved in 3 ml ofnitrobenzene. 1 mmol of an aryl aldehyde or heteroaryl aldehyde is addedto this. It is heated for 2-6 hours to 150° C. and allowed to cool. Theresidue is purified directly by column chromatography on silica gelwithout additional working-up.

[0185] General Operating Instructions 6:

[0186] Conversion of Carboxylic Acid Esters to Carboxylic Acid Amides

[0187] 0.36 mmol of an amine is dissolved in 3 ml of toluene and mixeddrop by drop with 0.18 ml of a 2 M solution of trimethylaluminum intoluene while being cooled in an ice bath. It is mixed with a solutionthat consists of 0.33 mmol of carboxylic acid methyl ester in 3 ml oftoluene, and it is stirred for 2 to 8 hours at 95° C. For working-up,water is added after cooling, it is extracted three times with ethylacetate, the combined organic phases are washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by columnchromatography on silica gel.

[0188] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0189] In the foregoing and in the following examples, all temperaturesare set forth uncorrected in degrees Celsius and, all parts andpercentages are by weight, unless otherwise indicated.

EXAMPLE 1

[0190] 6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yloxy]hexanoic Acid

[0191] a) 3-(4-Methylphenyl)amino-4-nitrophenol

[0192] 5.4 g of 3-fluoro-4-nitrophenol and 4.8 ml of 4-methylanilinewere mixed and stirred for 6 hours at 120° C. After cooling, it wastaken up in ethyl acetate and water and extracted three times with 1Naqueous hydrochloric acid. The combined aqueous phases were extractedthree times with ethyl acetate. The combined organic phases were driedon sodium sulfate, concentrated by evaporation in a vacuum, and theresidue was crystallized.

[0193] MS (EI): 244 (molecular ion peak)

[0194] b) 6-[3-(4-Methylphenyl)amino-4-nitrophenyl]oxyhexanoic AcidMethyl Ester

[0195] was obtained by reaction of 3-(4-methylphenyl)amino-4-nitrophenolwith 6-bromohexanoic acid methyl ester according to general operatinginstructions 3.

[0196] MS (EI): 372 (molecular ion peak)

[0197] c) 6-[14-Amino-3-((4-methylphenyl)amino)phenyl]oxy]hexanoic AcidMethyl Ester

[0198] was obtained by reaction of6-[3-(4-methylphenyl)amino-4-nitrophenyl]oxy-hexanoic acid methyl esteraccording to general operating instructions 1.

[0199] MS (EI): 342 (molecular ion peak)

[0200] d)6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid Methyl Ester

[0201] was obtained by reaction of6-[[4-amino-3-((4-methylphenyl)amino)-phenyl]oxy]hexanoic acid methylester with 3-pyridylcarbaldehyde according to general operatinginstructions 5.

[0202] MS (E1): 429 (molecular ion peak)

[0203] e)6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0204] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester according to general operating instructions 4.

[0205] MS (EI): 415 (molecular ion peak)

EXAMPLE 2

[0206]5-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0207] a) 5-[3-(4-Methylphenyl)amino-4-nitrophenyl]oxypentanoic AcidMethyl Ester

[0208] was obtained by reaction of 3-(4-methylphenyl)amino-4-nitrophenolwith 5-bromopentanoic acid methyl ester according to general operatinginstructions 3.

[0209] MS (E1): 358 (molecular ion peak)

[0210] b) 5-[[4-Amino-3-((4-methylphenyl)amino)phenyl]oxylpentanoic AcidMethyl Ester

[0211] was obtained by reaction of5-[3-(4-methylphenyl)amino-4-mitrophenyl]-oxypentanoic acid methyl esteraccording to general operating instructions 1.

[0212] MS (E1): 328 (molecular ion peak)

[0213] c)5-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid Methyl Ester

[0214] was obtained by reaction of5-[[4-amino-3-((4-methylphenyl)amino)-phenyl]oxy]pentanoic acid methylester with 3-pyridylcarbaldehyde according to general operatinginstructions 5.

[0215] MS (EI): 415 (molecular ion peak)

[0216] d)5-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0217] was produced by reaction of5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid methyl ester according to general operating instructions 4.

[0218] MS (EI): 401 (molecular ion peak)

EXAMPLE 3

[0219]4-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-H-benzimidazol-6-yl]oxy]butyricAcid

[0220] a) 4-[3-(4-Methylphenyl)amino-4-nitrophenyl]oxybutyric AcidMethyl Ester

[0221] was obtained by reaction of 3-(4-methylphenyl)amino-4-nitrophenolwith 4-bromobutyric acid methyl ester according to general operatinginstructions 3.

[0222] MS (EI): 344 (molecular ion peak)

[0223] b) 4-[[4-Amino-3-((4-methylphenyl)amino)phenyl]oxy]butyric AcidMethyl Ester

[0224] was obtained by reaction of4-[3-(4-methylphenyl)amino-4-nitrophenyl]-oxybutyric acid methyl esteraccording to general operating instructions 1.

[0225] MS (E1): 314 (molecular ion peak)

[0226] c)4-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyricAcid Methyl Ester

[0227] was obtained by reaction of4-[[4-amino-3-((4-methylphenyl)amino)-phenyl]oxy]butyric acid methylester with 3-pyridyl carbaldehyde according to general operatinginstructions 5.

[0228] MS (EI): 401 (molecular ion peak)

[0229] d)4-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyricAcid

[0230] was produced by reaction of4-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyricacid methyl ester according to general operating instructions 4.

[0231] MS (EI): 387 (molecular ion peak)

EXAMPLE 4

[0232]6-[[1-(4-Methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0233] a)6-[[1-(4-Methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid Methyl Ester

[0234] was obtained by reaction of6-[[4-amino-3-((4-methylphenyl)amino)-phenyl]oxy]hexanoic acid methylester with 4-pyridyl carbaldehyde according to general operatinginstructions 5.

[0235] MS (EI): 429 (molecular ion peak)

[0236] b)6-[[1-(4-Methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0237] was produced by reaction of6-[[1-(4-methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester according to general operating instructions 4.

[0238] MS (EI): 415 (molecular ion peak)

EXAMPLE 5

[0239]6-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0240] a)6-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid Methyl Ester

[0241] was obtained by reaction of6-[[4-amino-3-((4-methylphenyl)amino)-phenyl]oxy]hexanoic acid methylester with 3-thienyl carbaldehyde according to general operatinginstructions 5.

[0242] MS (EI): 434 (molecular ion peak)

[0243] b)6-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0244] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester according to general operating instructions 4.

[0245] MS (EI): 420 (molecular ion peak)

EXAMPLE 6

[0246]5-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0247] a)5-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid Methyl Ester

[0248] was obtained by reaction of5-[[4-amino-3-((4-methylphenyl)-amino)phenyl]oxy]pentanoic acid methylester with 3-thienyl-carbaldehyde according to general operatinginstructions 5.

[0249] MS (EI): 420 (molecular ion peak)

[0250] b)5-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0251] was produced by reaction of5-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid methyl ester according to general operating instructions 4.

[0252] MS (EI): 406 (molecular ion peak)

EXAMPLE 7

[0253]4-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyricAcid

[0254] a)4-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyricAcid Methyl Ester

[0255] was obtained by reaction of4-[[4-amino-3-((4-methylphenyl)-amino)phenyl]oxy]butyric acid methylester with 3-thiophene carbaldehyde according to general operatinginstructions 5.

[0256] MS (EI): 406 (molecular ion peak)

[0257] b)4-[[1-(4-Methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyricAcid

[0258] was produced by reaction of4-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyricacid methyl ester according to general operating instructions 4.

[0259] MS (EI): 392 (molecular ion peak)

EXAMPLE 8

[0260] 5-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0261] a) 4-Methoxy-N²-phenyl-o-phenylenediamine

[0262] was obtained by reaction of (5-methoxy-2-nitrophenyl)phenylamine[Kottenhahn et al.; J. Org. Chem.; 28; 1963; 3114, 3118; Banthorpe;Cooper; J. Chem. Soc. B; 1968; 605] according to general operatinginstructions 1.

[0263]¹H-NMR (CDCl₃): δ=3.42 ppm s (broad) (2H); 3.72 s (3H); 5.33 s(broad)(1H); 6.56 dd (J=10, 2 Hz, 1H); 6.76 d (J=10 Hz, 1H); 6.79 d (J=2Hz, 1H); 6.82-6.90 m (3H); 7.25 dd (J=8, 8 Hz, 2H).

[0264] b) 6-Methoxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole

[0265] was obtained by reaction of4-methoxy-N²-phenyl-o-phenylenediamine with thiophene-3-carbaldehydeaccording to general operating instructions 5.

[0266] MS (EI): 306 (molecular ion peak)

[0267] c) 6-Hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole

[0268] was obtained by reaction of6-methoxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole according to generaloperating instructions 2.

[0269] MS (EI): 292 (molecular ion peak)

[0270] d) 5-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl oxy]pentanoicAcid Methyl Ester

[0271] was obtained by reaction of6-hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole with 5-bromopentanoicacid methyl ester according to general operating instructions 3.

[0272] MS (EI): 406-(molecular ion peak)

[0273] e) 5-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0274] was obtained by reaction of5-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoic acidmethyl ester according to general operating instructions 4.

[0275] MS (E1): 392 (molecular ion peak)

EXAMPLE 9

[0276] 4-[[-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyric Acid

[0277] a) 4-[fl-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyricAcid Methyl Ester

[0278] was obtained by reaction of6-hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole with 4-bromobutanoicacid methyl ester according to general operating instructions 3.

[0279] MS (EI): 392 (molecular ion peak)

[0280] b) 4-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyricAcid

[0281] was obtained by reaction of4-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyric acid methylester according to general operating instructions 4.

[0282] MS (E1): 378 (molecular ion peak)

EXAMPLE 10

[0283] 6-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoic Acid

[0284] a) 6-[1-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid Methyl Ester

[0285] was obtained by reaction of6-hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole with 6-bromohexanoicacid methyl ester according to general operating instructions 3.

[0286] MS (EI): 420 (molecular ion peak)

[0287] b) 6-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0288] was obtained by reaction of6-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methylester according to general operating instructions 4.

[0289] MS (EI): 406 (molecular ion peak)

EXAMPLE 11

[0290]6-[[1-(4-Fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0291] a) (5-Chloro-2-nitrophenyl)-(4-fluorophenyl)amine

[0292] 50 g of 1-chloro-3,4-dinitrobenzene in 250 ml of ethanol is mixedwith 50 ml of 4-fluoroaniline and stirred for 35 hours at 60° C. Afterconcentration by evaporation to half the volume, water anddichloromethane are divided up. After the organic phase is washed with1N aqueous hydrochloric acid, it is dried on sodium sulfate, filteredand concentrated by evaporation. After chromatography on silica gel,62.33 g (5-chloro-2-nitrophenyl)-(4-fluorophenyl)amine is obtained.

[0293]¹H-NMR (CDCl₃): δ=6.71 dd (J 9, 2 Hz, 1H); 6.97 d (J=2 Hz, −1H);7.13 dd (J=9, 9 Hz, 2H); 7.22 dd (J=9, 6 Hz, 2H); 8.15 d (J=10 Hz, 1H);9.45 s (br)(1H).

[0294] b) (5-Methoxy-2-nitrophenyl)-(4-fluorophenyl)amine

[0295] 36.44 g (5-chloro-2-nitrophenyl)-(4-fluorophenyl)amine was addedto a solution that consists of 6.6 g of sodium in 450 ml of methanol,and it was refluxed for 16 hours. After another 30 hours of stirring at60° C., it was cooled, and the crystalline product was suctioned off. 34g of (5-methoxy-2-nitrophenyl)-(4-fluorophenyl)amine was obtained.

[0296]¹H-NMR (CDCl₃): δ=3.72 s (3H); 6.44 dd (J=9, 2 Hz, 1H); 6.48 d(J=2 Hz, 1H); 7.13 dd (J=9, 9 Hz, 2H); 7.27 dd (9, 6 Hz, 2H); 8.20 d(J=9 Hz, 1H); 9.65 s (br)(1H).

[0297] c) N²-(4-Fluorophenyl)-4-methoxybenzene-1,2-diamine

[0298] 33.5 g (0.128 ml) of(5-methoxy-2-nitrophenyl)-(4-fluorophenyl)amine was reacted according togeneral operating instructions 1. The crude product was furtherprocessed without purification.

[0299]¹H-NMR (CDCl₃): δ=3.70 ppm s (3H); 6.49 d(br) (J=9 Hz, 1H); 6.68 d(J 2 Hz, 1H); 6.78-6.97 m (5H).

[0300] d) 6-Methoxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole

[0301] 7.48 g of thiophene-3-aldehyde was stirred in 65 ml of 40% NaHSO₃solution for two hours. After 15 g ofN²-(4-fluorophenyl)-4-methoxybenzene-1,2-diamine in 50 ml of ethanol wasadded, it was boiled for 4 hours, and stirring was continued overnight.The batch was dispersed between water and ethyl acetate, and the organicphase was washed with water. After drying on sodium sulfate andconcentration by evaporation of the filtrate, 18.1 g of crude6-methoxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole is obtained.

[0302] Flash point 154-158° C.

[0303] e) 6-Hydroxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole

[0304] 18 g (55.5 mmol) of6-methoxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole is reactedanalogously to general operating instructions 2. 12.65 g (40 mmol) ofcrude 6-hydroxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole wasobtained.

[0305] Flash point 212-218° C.

[0306] f)6-[[1-(4-Fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid Methyl Ester

[0307] 6-Hydroxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole wasreacted with 6-bromo-hexanoic acid methyl ester according to generaloperating instructions 3.

[0308] Flash point 131-134° C.

[0309] g) 6-[[1-(4-Fluorophenyl)-2-(3-thienyl-1H-benzimidazol-6-yl oxyhexanoic acid was obtained by reaction of6-[[1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester according to general operating instructions 4.

[0310] Flash point 170-175° C.

EXAMPLE 12

[0311]5-[1-(4-Fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0312] a)5-[[1-(4-Fluorophenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid Methyl Ester

[0313] 6-Hydroxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole wasreacted according to general operating instructions 3 with5-bromopentanoic acid methyl ester.

[0314] Flash point 90.5-92.5.° C.

[0315] b)5-[[11-(4-Fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0316]5-[[[-(4-Fluorophenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid methyl ester was reacted according to general instructions 4.

[0317] Flash point 184-189° C.

EXAMPLE 13

[0318]6-[[1-(4-Fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0319] a) 6-Methoxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole

[0320] N²-(4-Fluorophenyl)-4-methoxybenzene-1,2-diamine was reactedanalogously to Example 11d with pyridine-3-carbaldehyde.

[0321] Flash point 132.5-134° C.

[0322] b) 6-Hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole

[0323] 6-Methoxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole wasreacted according to general operating instructions 2.

[0324] Flash point 238-241° C.

[0325] c)6-[[1-(4-Fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid Methyl Ester

[0326] 6-Hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole wasreacted with 6-bromohexanoic acid methyl ester according to generaloperating instructions 3.

[0327] Flash point 105.5-111.5° C.

[0328] d)6-[1-(4-Fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0329] was obtained by reaction of6-[[1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester according to general operating isntructions 4.

[0330] Flash point 127.5-129° C.

EXAMPLE 14

[0331]5-[[1-(4-Fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0332] a)5-[1-(4-Fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid Methyl Ester

[0333] 6-Hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole wasreacted with 5-bromo-pentanoic acid methyl ester according to generaloperating instructions 3.

[0334] Flash point 52-55° C.

[0335] b)5-[[1-(4-Fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0336] was obtained by reaction of 5-[[1(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoic acidmethyl ester according to general operating instructions 4.

[0337] Flash point 181.5-183° C.

EXAMPLE 15

[0338] 5-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicAcid

[0339] a) 6-Methoxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole

[0340] was obtained by reaction of4-methoxy-N²-phenyl-o-phenylenediamine with pyridine-3-carbaldehydeaccording to general operating instructions 5.

[0341] MS (EI): 301 (molecular ion peak)

[0342] b) 6-Hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole

[0343] was obtained by reaction of6-methoxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole according to generaloperating instructions 2.

[0344]¹H-NMR (D₆-DMSO): δ=6.52 ppm d (J 2 Hz, 1H); 6.81 dd (J=8, 2 Hz,1H); 7.34-7.48 m (3H); 7.53-7.68 m (4H); 7.80 (ddd, J 8, 2, 1 Hz, 1H);8.53 dd (J=2, 1 Hz, 1H); 8.67 d (J 1 Hz, 1H); 9.42 (s, 1H).

[0345] c)5-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoic AcidMethyl Ester

[0346] was obtained by reaction of6-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with5-bromopentanoic acid methyl ester according to general operatinginstructions 3.

[0347] MS (EI): 401 (molecular ion peak)

[0348] d)5-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoic Acid

[0349] was obtained by reaction of5-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoic acidmethyl ester according to general operating instructions 4.

[0350]¹H-NMR (CD₃OD): δ=1.72-1.88 m (4H); 2.30 t (J=8 Hz, 2H); 3.98 t(J=8 Hz, 2H); 6.72 ppm d (J=2 Hz, 1H); 7.03 dd (J=8, 2 Hz, 1H);7.40-7.48 m (3H); 7.55-7.65 m (3H); 7.70 (d, J=8 Hz, 1H); 7.92 ddd (J 8,2, 1 Hz, 1H); 8.53 dd (J 8, 2 Hz, 1H); 8.70 dd (J=2, 1 Hz, 1H).

EXAMPLE 16

[0351] 4-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyricAcid

[0352] a) 4-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyricAcid Methyl Ester

[0353] was obtained by reaction of6-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with 4-bromobutanoicacid methyl ester according to general operating instructions 3.

[0354] MS (EI): 387 (molecular ion peak)

[0355] b) 4-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyricAcid

[0356] was obtained by reaction of4-[[1-phenyl-2-(3-pyridinyl)-H-benzimidazol-6-yl]oxy]butyric acid methylester according to general operating instructions 4.

[0357] MS (EI): 373 (molecular ion peak)

EXAMPLE 17

[0358] 6-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0359] a) 6-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl oxy]hexanoicAcid Methyl Ester

[0360] was obtained by reaction of6-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with 6-bromohexanoicacid methyl ester according to general operating instructions 3.

[0361] MS (EI): 415 (molecular ion peak)

[0362] b) 6-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0363] was obtained by reaction of6-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoic acidmethyl ester according to general operating instructions 4.

[0364] MS (EI): 401 (molecular ion peak)

EXAMPLE 18

[0365]N-(3-Methoxypropyl)-6-[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0366] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester with 3-methoxypropylamine according to generaloperating instructions 6.

[0367] MS (EI): 486 (molecular ion peak)

EXAMPLE 19

[0368]6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]-1-morpholin-1-ylhexan-1-one

[0369] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester with morpholine according to general operatinginstructions 6.

[0370] MS (EI): 442 (molecular ion peak)

EXAMPLE 20

[0371]N-Methyl-6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0372] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester with N-methylamine hydrochloride according to generaloperating instructions 6.

[0373] MS (E1): 428 (molecular ion peak)

EXAMPLE 21

[0374]N,N-Dimethyl-6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0375] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester with dimethylamine hydrochloride according to generaloperating instructions 6.

[0376] MS (EI): 442 (molecular ion peak)

EXAMPLE 22

[0377]6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0378] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester with ammonium chloride according to general operatinginstructions 6.

[0379] MS (EI): 414 (molecular ion peak)

EXAMPLE 23

[0380]N-Cyclopropyl-6-[[1-(4-methylphenyl)-2-(-3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0381] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester with cyclopropylamine according to general operatinginstructions 6.

[0382] MS (EI): 459 (molecular ion peak)

EXAMPLE 24

[0383]N-Methyl-6-[[i-(4-methylphenyl)-2-(-3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanamide

[0384] was produced by reaction of6-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester with N-methylamine hydrochloride according to generaloperating instructions 6.

[0385] MS (EI): 433 (molecular ion peak)

EXAMPLE 25

[0386]N-(2-Methoxyethyl)-5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamide

[0387] was produced by reaction of5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid methyl ester with 2-methoxyethylamine according to generaloperating instructions 6.

[0388] MS (EI): 458 (molecular ion peak)

EXAMPLE 26

[0389]N,N-Dimethyl-5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamide

[0390] was produced by reaction of5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid methyl ester (Example 56c) with dimethylamine according to generaloperating instructions 6.

[0391] MS (EI): 428 (molecular ion peak)

EXAMPLE 27

[0392]5-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamide

[0393] was produced by reaction of5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid methyl ester with ammonium chloride according to general operatinginstructions 6.

[0394] MS (E1): 400 (molecular ion peak)

EXAMPLE 28

[0395]6-[[1-(4-Methylphenyl)-2-(2-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0396]a)-6-[[1-(4-Methylphenyl)-2-(2-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid Methyl Ester

[0397] was obtained by reaction of6-[[4-amino-3-((4-methylphenyl)amino)phenyl]-oxy]hexanoic acid methylester with 2-thienylcarbaldehyde according to general operatinginstructions 5.

[0398] MS (EI): 434 (molecular ion peak)

[0399] b)6-[[1-(4-Methylphenyl)-2-(2-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicAcid

[0400] was produced by reaction of6-[[1-(4-methylphenyl)-2-(2-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid methyl ester according to general operating instructions 4.

[0401] MS (EI): 420 (molecular ion peak)

EXAMPLE 29

[0402] Inhibition of Microglia Activation

[0403] For in vitro production of Aβ-activated microglia, primary ratmicroglia with synthetic Aβ-peptide are incubated:

[0404] For simulation of Aβ deposits, synthetic Aβ peptide is dried on96-hole tissue culture plates. A peptide stock solution is diluted by 2mg/ml of H_(201:50) in H₂O. To coat the 96-hole plates, 30 μl of thisdilute peptide solution/hole is used, and it is dried overnight at roomtemperature.

[0405] Primary rat microglia are harvested by mixed glia cultures, whichwere obtained from P3 rat brains. In-the production of mixed gliacultures, the brains are taken from 3-day-old rats, and meninges areremoved. The isolation of cells is achieved by trypsinization (0.25%trypsin solution, 15 minutes, 37° C.)). After undigested tissuefragments are separated with the aid of a 40 μm nylon mesh, the isolatedcells are centrifuged off (800 rpm/10 min). The cell pellet isresuspended in the culture medium and moved into 100 ml tissue cultureflasks (1 brain/tissue culture flask). The cultivation of the cells iscarried out over a period of 5 to 7 days in Dulbeccos Modified EagleMedium (DMEM, with glutamine), supplemented with penicillin (50 U/ml),streptomycin (40 μg/ml) and 10% (v/v) fetal calf serum (FCS) at 37° C.and 5% CO₂. During this incubation, an adhesive cellular film is formed,which mainly consists of astrocytes. Microglia proliferate asnon-adhesive or weakly adhesive cells on the latter and are harvestedvia shaking incubation (420 rpm, 1 hour).

[0406] To activate the microglia by Aβ-peptide, 2.5×10⁴ microglia/holeare grown on the Aβ-coated tissue culture plates and incubated over aperiod of 7 days in DMEM (with glutamine), supplemented with penicillin(50 U/ml), streptomycin (40 μg/ml) and 10% (v/v) fetal calf serum (FCS)at 37° C. and 5% CO₂. On day 5, a compound according to the invention isadded at various concentrations (0.1, 0.3, 1.3 and 10 μM).

[0407] To quantify the microglia reactivity, the metabolic activity ismeasured on cultivation day 7 via the reduction of MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(sulfophenyl)-2H-tetrazolium),Owen's reagent, Baltrop, J. A. et al. Bioorg. & Med. Chem. Lett., 1,6111 (1991)). The percentage of inhibition relates to a control that istreated only with DMSO. The compounds according to the invention inhibitthe microglia activation.

EXAMPLE 30

[0408] Cerebral Brain Infarction in Rats (MCAO Model)

[0409] The compounds according to the invention were tested for in vivoactivity in an animal model for cerebral ischemia (stroke), the MCAO(permanent middle cerebral artery occlusion) model. One-sidedobstruction of the middle cerebral artery (MCA) triggers a braininfarction, which is caused by the fact that the corresponding area ofthe brain is undernourished with oxygen and nutrients. The result ofthis undernourishment is a pronounced cellular degeneration and,subsequently, a strong microglia activation. This microglia activationreaches its maximum only after several days, however, and can last forseveral weeks. To test the substances, the compounds according to theinvention were administered intraperitoneally 1-6 days after occlusion.On day 7, the animals were perfused and sacrificed. The extent of themicroglia activation was measured by a modified immunohistochemicalmethod. Vibratom sections of fixed brains were incubated with antibodiesthat detect the CR3 complement receptor or the MHCII complex onactivated microglia. The quantification of the primary antibody bond wascarried out by an enzyme-coupled detection system. The treatment withthe compounds according to the invention resulted in a reduction ofmicroglia activation in the brain hemisphere affected by the braininfarction.

EXAMPLE 31

[0410] Inhibition of the TNFα Production and IL 12 Production in THP-1Cells

[0411] The inhibition of the cytokine production is visualized, forexample, by measuring TNFα and interleukin 12 in lipopolysaccharide(LPS)-stimulated THP-1 cells.

[0412] For this purpose, 2.5×10⁶ THP-1 cells (American Type CultureCompany, Rockville, Md.)/ml of RPMI 1640 medium (Life Technologies)/10%FCS (Life Technologies, Cat. No. 10270-106) are grown on 96-holeflat-bottomed cell culture plates (TPP, Product No. 9296) (100 μl/hole).The compounds according to the invention are added at variousconcentrations and pre-incubated for 30 minutes. The pre-dilution of thetest substances was performed in the incubation medium. The addition ofthe test substances is carried out as a 2×concentrated substancesolution (100 μl/hole). The stimulation of the cells was carried outovernight at 37° C. with 0.11 g/ml of LPS (Sigma L2630, of E. ColiSerotype 0111.B4). Then, the medium was harvested, and the amount ofTNFα or the amount of interleukin 12 was quantitatively determined. Tomeasure the TNFα, a commercially available TNFα kit of the CIS BioInternational Company was used (Product No. 62TNFPEB). The amount ofinterleukin 12 was implemented with the aid of the ORIGEN Technologies(IGEN International, Inc., Gaithersburg, Md.). The calculated IC50 valuecorresponds to the concentration of test substance that is required toreach a 50% inhibition of the maximum TNFα or interleukin 12 production.

[0413] The compounds according to the invention inhibit the TNFαproduction and interleukin 12 production in lipopolysaccharide(LPS)-stimulated THP-1 cells.

EXAMPLE 32

[0414] Inhibition of the IFNγ Production of Peripheral Mononuclear BloodCells

[0415] To visualize the effect of the substances on T-cell activation,for example, the measurement of the IFNγ-secretion is used.

[0416] To isolate peripheral mononuclear cells, human whole blood wasused (drawing of blood via Na-citrate S-monovettes “Coagulation 9 NC/10ml”/Sarstedt). The build-up of the blood cells was accomplished with theaid of density gradient centrifuging: For this purpose, 15 ml ofHistopaque 1077 (Sigma, Cat. No. H8880) in LEUCOSEP tubes (Greiner, Cat.No. 227290) is introduced and centrifuged for 30 seconds at 1000 g.Then, 15 ml of whole blood is added and centrifuged for 10 minutes at1000 g. Finally, the upper plasma layer is pipetted off and thesubjacent cell layer (peripheral mononuclear blood cells) is transferredin 15 ml sample tubes (Falcon) and then washed several times with 10 mlof HBSS (HANKS Balanced Solution) (without Mg²⁺ and Ca²⁺), Cat. No.14175-53). Finally, the cell pellet is resuspended in culture mediumRPMI 1640+25 mmol of Hepes (Life Technologies Cat. No. 52400-04110% FCS(Life Technologies, Cat. No. 10270-106), 0.4% penicillin-streptomycinsolution (Life Technologies, Cat. No. 15140-106) (1×10⁶ cells/ml). Ineach case, 100 μl of cell suspension solution was dispersed on 96-holeflat-bottomed cell culture plates (TPP, Product No. 9296) and stimulatedwith 2.5 μg/ml of anti-CD3 antibody. The substances according to theinvention were added at various concentrations and pre-incubated for 30minutes. The stimulation of the cells was carried out over a period of24 hours. Then the medium was harvested, and the amount of IFNγ wasdetermined quantitatively. The amount of IFNγ was determined with theaid of ORIGEN Technologies (IGEN International, Inc., Gaithersburg,Md.). The calculated IC50 value corresponds to the concentration of testsubstance that is required to reach a 50% inhibition of the maximum IFNγproduction.

[0417] The compounds according to the invention inhibit the INFγproduction of peripheral mononuclear blood cells.

EXAMPLE 33

[0418] Inhibition of the TNFα and IL-12 HD Production of PeripheralMononuclear Blood Cells

[0419] The inhibition of the TNFα and IL-12 HD p70 production isvisualized by, for example, measuring TNFα and IL-12 HD p70 inperipheral mononuclear blood cells that are stimulated withlipopolysaccharide (LPS) and interferon gamma (IFNγ).

[0420] To isolate peripheral mononuclear blood cells, human whole bloodwas used (drawing of blood via Na-Citrate S-monovettes “Coagulation 9NC/10 ml”/Sarstedt). The build-up of the lymphocytes and monocytes wasaccomplished with the aid of the density gradient centrifuging: For thispurpose, 15 ml of Histopaque-1077 (Sigma, Cat. No. H8880) is introducedinto 50 ml LEUCOSEP tubes (Greiner, Cat. No. 227290) and forced downwardby centrifuging for 30 seconds at 250 g by the frits that are containedin the tubes. Then, 20 ml of whole blood is added and centrifuged for 15minutes at 800 g and at room temperature. After centrifuging, thesupernatant (plasma and thrombocytes) is pipetted off and discarded, andthe subjacent cell layer (lymphocytes and monocytes) is transferred into50 ml centrifuging tubes (Falcon) and then washed 3×in culture mediumVLE RPMI 1640 (Seromed, No. FG1415) (centrifuging in each case for 10minutes at 250 g, room temperature). Finally, the cell pellet isresuspended in culture medium VLE RPMI 1640 (Seromed, No. FG1415), 10%FCS (Life Technologies, Cat. No. 16000-044, low endotoxin,heat-inactivated for 1 hour, 56° C.), 50 μg/ml ofpenicillin-streptomycin solution (Life Technologies, Cat. No. 15140-106)and set at 3×10⁶ cells/ml after cell counting by means of trypan bluestaining. In each case, 100 μl of cell suspension solution was dispersedon 96-hole flat-bottomed cell culture plates (Costar, Product No. 3599).In each case, 100 μl of 3×-concentrated stimulation solution (3 μg/ml ofLPS of E. coli Serotype 0127:B8: Sigma, Cat. No. L-4516 and 300 ng/ml ofIFNγ 1b, Imukin, Boehringer Ingelheim) was added to it. The substancesaccording to the invention were added at various concentrations as3×-concentrated substance solution (100 μl/well). The stimulation of thecells was carried out at 37° C. and 5% CO₂ over a period of 24 hours.Then, the cell culture supernatant was harvested, and the concentrationsof TNFα and IL-12 HD p70 were determined by means of commerciallyavailable ELISA Kits of the BioSource International Company (TNF-αEASIA, Cat. No. KAC1752) and R & D Systems (Quantikine™ HS IL-12, Cat.No. HS 120).

[0421] The calculated IC₅₀ value corresponds to the concentration oftest substance that is required to reach a 50% inhibition of the maximumTNFα- or interleukin 12 HD p70 production.

[0422] The compounds according to the invention inhibit the TNFα andIL-12 HD p70 production of peripheral mononuclear blood cells.

EXAMPLE 34

[0423] Induction of IL-10 Production of Peripheral Mononuclear BloodCells

[0424] The induction of IL-10 production is visualized by, for example,measuring L-10 in peripheral mononuclear blood cells that are stimulatedin phtyohemagglutinin (PHA) or lipopolysaccharide (LPS).

[0425] To isolate peripheral mononuclear blood cells, human whole bloodwas used (drawing of blood via Na-Citrate S-monovettes “Coagulation 9NC/10 ml”/Sarstedt). The build-up of the lymphocytes and monocytes wasaccomplished with the aid of the density gradient centrifuging: For thispurpose, 15 ml of Histopaque-1077 (Sigma, Cat. No. H8880) in 50 mlLEUCOSEP tubes (Greiner, Cat. No. 227290) is introduced and forceddownward by centrifuging for 30 seconds at 250 g by the frits that arecontained in the tubes. Then, 20 ml of whole blood is added andcentrifuged for 15 minutes at 800 g and at room temperature. Aftercentrifuging, the supernatant (plasma and thrombocytes) is pipetted offand discarded, and the subjacent cell layer (lymphocytes and monocytes)in 50 ml centrifuging tubes (Falcon) is transferred and then washed 3×inculture medium VLE RPMI 1640 (Seromed, No. FG1415) (centrifuging in eachcase for 10 minutes at 250 g, room temperature). Finally, the cellpellet is resuspended in culture medium VLE RPMI 1640 (Seromed, No.FG1415), 10% FCS (Life Technologies, Cat. No. 16000-044, low endotoxin,heat-inactivated for 1 hour, 56° C.), 50 μg/ml ofpenicillin-streptomycin solution (Life Technologies, Cat. No. 15140-106)and set at 3×10⁶ cells/ml after cell counting by means of trypan bluestaining. In each case, 100 μl of cell suspension solution was dispersedon 96-hole flat-bottomed cell culture plates (Costar, Product No. 3599).In each case, 100 μl of 3×-concentrated stimulation solution (3 μg/ml ofLPS of E. coli Serotype 0127:B8; Sigma, Cat. No. L-4516 or 300 μg/ml ofP+A-L, Biochrom KG, Cat. No. M5030) was added to it. The substancesaccording to the invention were added at various concentrations as3×-concentrated substance solution (100 μl/well). The stimulation of thecells was carried out at 37° C. and 5% CO₂ over a period of 24 hours.Then, the cell culture supernatant was harvested, and IL-10 wasdetermined quantitatively. The IL-10 concentration was determined bymeans of a commercially available ELISA Kit of the BioSourceInternational Company (human IL-10, Cat. No. KHCO0101C). The calculatedEC₅₀ value corresponds to the concentration of test substance that isrequired to increase the IL-10 secretion by 50% of the maximum increase.

[0426] The compounds according to the invention increase the IL-10production of peripheral mononuclear blood cells.

[0427] The entire disclosures of all applications, patents andpublications, cited herein and of corresponding German Application No.10207844.0, filed Feb. 15, 2002, and U.S. Provisional Application SerialNo. 60/357,834, filed Feb. 21, 2002 are incorporated by referenceherein.

[0428] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0429] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. Benzimidazole derivatives of general formula I

in which R¹ is a phenyl group that is optionally substituted with up tothree of the following substituents, independently of one another: F,Cl, Br, I OH, OR⁴, OCOR⁴ SR⁴, SOR⁴, SO₂R⁴, R⁴, NH₂, NR⁴,NR⁴R^(4′) or twoadjacent substituents at R¹ together form an O—CH₂—O—, —O—CH₂—CH₂—O— or—CH₂—CH₂—CH₂— group, R² is a monocyclic or bicyclic 5- to 10-memberedheteroaryl group with 1-2 heteroatoms, selected from N, S and O, whichoptionally is substituted with up to two of the following substituents,independently of one another: F, Cl, Br, I OH, OR⁴, OCOR⁴, COR⁴, SR⁴,SOR⁴, SO₂R⁴, R⁴, or two adjacent substituents at R² together form an—O—CH₂—O—, —O—CH₂—CH₂—O— or —CH₂—CH₂—CH₂— group, R³ is H, OH orO—C₁₋₆-alkyl, R⁴ and R^(4′), independently of one another, areC₁₋₄-perfluoroalkyl or C₁₋₆-alkyl, A is a C₂₋₆-alkylene group, whichoptionally is substituted with ═O, OH, O—C₁₋₃-alkyl, NH₂, NH—C₁₋₃-alkyl,NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂, and N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), B isCOOH, CONH₂, CONHNH₂, CONHR⁵, CONR⁵R⁵, in each case bonded to a carbonatom of group A, R⁵ and R⁵′, independently of one another, are in eachcase a radical, selected from the group that comprises C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkinyl, whereby a C atom can be exchanged for O, S,SO, SO₂, NH, N—C₁₋₃-alkyl or N—C₁₋₃-alkanoyl, and also(C₀₋₃-alkanediyl-C₃₋₇-cycloalkyl), whereby in a five-membered cycloalkylring, a ring member can be ring N or ring 0, and in a six- orseven-membered cycloalkyl ring, one or two ring members in each case canbe ring-N atoms and/or ring-O atoms, whereby the ring-N atoms optionallycan be substituted with C₁₋₃-alkyl or C₁₋₃-alkanoyl, as well as also(C₀₋₃-alkanediyl-phenyl) and (C₀₋₃-alkanediyl-heteroaryl), whereby theheteroaryl group is five- or six-membered and contains one or twoheteroatoms that are selected from the group that comprises N, S and O,whereby all above-mentioned alkyl and cycloalkyl radicals optionally canbe substituted with up to two radicals that are selected from the groupthat comprises CF₃, C₂F₅, OH, O—C₁₋₃-alkyl, NH₂, NH—C₁₋₃-alkyl,NH—C₁₋₃-alkanoyl, N(C₁₋₃-alkyl)₂, N(C₁₋₃-alkyl)(C₁₋₃-alkanoyl), COOH,CONH₂ and COO—C₁₋₃-alkyl, and all above-mentioned phenyl and heteroarylgroups optionally can be substituted with up to two radicals that areselected from the group that comprises F, Cl, Br, CH₃, C₂H₅, OH, OCH₃,OC₂H₅, NO₂, N(CH₃)₂, CF₃, C₂F₅ and SO₂NH² or R⁵ and R^(5′) together withthe N atom form a five- to seven-membered heterocyclic ring that cancontain another N or O or S atom and that can be substituted withC₁₋₄-alkyl, (C₀₋₂-alkanediyl-C₁₋₄-alkoxy), C₁₋₄-alkoxycarbonyl,aminocarbonyl or phenyl as well as their optical or geometric isomers ortautomeric forms or pharmaceutically applicable salts, whereby thefollowing compounds are ruled out:6-[[1-Phenyl-2-(pyridin-4-yl)-H-benzimidazol-6-yl]oxy]hexanoic acid,6-[[1-phenyl-2-(benzothien-2-yl)-1H-benzimidazol-6-yl]oxy]hexanoic acid.2. Benzimidazoles according to claim 1, characterized in that R¹ is aphenyl group that optionally is substituted with up to two of thefollowing substituents, independently of one another: F, Cl, OH, OR⁴,OCOR⁴ SR⁴, R⁴ or two adjacent substituents at R¹ form an —O—CH₂—O— or—CH₂—CH₂—CH₂-group.
 3. Benzimidazoles according to claim 1 or 2, whereinR² is a monocyclic 5- to 6-membered heteroaryl group with 1-2heteroatoms, selected from the group that comprises N, S and O, whichoptionally is independently substituted with up to two of the followingsubstituents: F, C¹, OR⁴, OCOR⁴ SR⁴, SOR⁴, SO₂R⁴, R⁴ or two adjacentsubstituents at R² form an —O—CH₂—O— or —CH₂—CH₂—CH₂-group. 4.Benzimidazoles according to one of claims 1-3, wherein R³ is H. 5.Benzimidazoles according to one of claims 1-4, wherein R⁴ and R⁴′,independently of one another, are C₁₋₂ perfluoroalkyl, and C₁₋₄ alkyl.6. Benzimidazoles according to one of claims 1-5, wherein R⁵ and R⁵′,independently of one another, are C₁₋₆ alkyl, whereby a carbon atom canbe exchanged for O, S, SO, or SO², C₃₋₅ cycloalkyl-C₀₋₃ alkylene,whereby in a 5-membered cycloalkyl ring, a ring member can be an N or anO, whereby the ring nitrogen optionally is substituted with C₁₋₃ alkylor C₁₋₃ alkanoyl, C₀₋₂ alkylene-(5- to 6-membered heteroaryl with 1-2heteroatoms from N, S and O), whereby all above-mentioned alkyl andcycloalkyl radicals can be substituted with CF₃, OH, NH2, NH C₁₋₃ alkyl,NH C₁₋₃ alkanoyl, N(C₁₋₃alkyl)₂, N(C₁₋₃ alkyl)(C₁₋₃ alkanoyl), COOH,CONH₂ and all above-mentioned heteroaryl groups with one or twosubstituents from the group that consists of F, Cl, CH₃, C₂H₅, OCH₃,OC₂H₅, CF₃, C₂F₅, or R⁵ and R^(5′) together with the nitrogen atom forma 5- to 7-membered heterocyclic compound, which can contain anotheroxygen, nitrogen or sulfur atom and can be substituted with C₁₋₄-alkylor C₁₋₄-alkoxy-C₀₋₂-alkyl.
 7. Benzimidazoles according to one of claims1-6, wherein A is straight-chain C₃₋₆-alkylene.
 8. Benzimidazolesaccording to one of claims 1-5, 7, wherein B is COOH or CONH₂ in eachcase bonded to a carbon atom of group A. 9.6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid4-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyricacid6-[[1-(4-methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid6-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid5-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid4-[[1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyricacid 5-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoic acid4-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]butyric acid6-[[1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid6-[[1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid5-[[1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid 6-[[1(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid5-[[1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid 5-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoicacid 4-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]butyric acid6-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoic acidN-(3-methoxypropyl)-6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]-1-morpholin-1-ylhexan-1-oneN-methyl-6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamideN,N-dimethyl-6-[[1-(4-methyphenyl)-2-(3-pyridinyl)-1H-benzimidazo1-6-yl]oxy]hexanamide6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamideN-cyclopropyl-6-[[1-(4-methylphenyl)-2-(3-thieny)-1H-benzimidazol-6-yl]oxy]hexanamideN-methyl-6-[[1-(4-methylphenyl-2-(3-thienyl)-1H-benzimidazol-6-yl]oxy]hexanamide6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]-1-(thiazolidin-3-yl)-hexan-1-oneN-(2-methoxyethyl)-5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamideN,N-dimethyl-5-[[1-(4-methyphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamide5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-H-benzimidazol-6-yl]oxy]pentanamide6-[[1-(4-methylphenyl)-2-(2-thienyl)-1H-benzimidazol-6-yl]oxy]hexanoicacid according to claim
 1. 10. Use of a compound according to one ofclaims 1-9 for the production of a pharmaceutical agent for treating orpreventing diseases that are associated with a microglia activation. 11.Use according to claim 10 for treating or preventing inflammatory,allergic, infectious or autoimmune diseases.
 12. Pharmaceutical agentsthat are characterized in that they contain one or more compoundsaccording to one of claims 1-9 and one or more vehicles and/oradjuvants.